Optimizing Pediatric Dosing: A Developmental Pharmacologic Approach

Gail D. Anderson, Ph.D.; Anne M. Lynn, M.D.

Disclosures

Pharmacotherapy. 2009;29(6):680-690. 

In This Article

Hepatic Metabolism

Based on pharmacokinetic models of hepatic elimination,[21] hepatic clearance depends on protein binding, activity of metabolic enzymes (intrinsic clearance), and hepatic blood flow. Clearance of drugs with low extraction ratios reflects both protein binding and intrinsic clearance. For drugs with high extraction ratios, clearance is a function of hepatic blood flow.

Metabolic enzymes most commonly involved in drug metabolism are those of the CYP, uridine diphosphate glucuronosyltransferase (UGT), and N-acetyltransferase (NAT) families. Enzymatic activity is subject to genetic, physiologic, and environmental effects. Genetic polymorphisms can result in normal, inactive, reduced, or increased activity of various isoenzymes. For isoenzymes for which data are available, genotype is unrelated to phenotype at birth but develops as the enzymes mature.

CYP1A2

At birth, expression of CYP1A2 is negligible, reaching 50% of adult expression by approximately 0.9 years of age.[22] This isoenzyme accounts for approximately 90% of the metabolism of caffeine, a probe drug used to study CYP1A2 activity.[23] Clearance of caffeine is decreased in the neonate then increases in the young infant, reaching the adult rate of elimination by 5–6 months of age.[24] Results of the caffeine breath test to measure caffeine clearance are 50% higher in children aged 3–9 years and 33% higher in children and adolescents aged 9–15 years than in adults.[25]

Theophylline is classically characterized as a CYP1A2 substrate with minor metabolism by CYP2E1 and CYP3A4. Clearance of theophylline is approximately 50% of adult levels in neonates. It increases to 50% greater than adult values by 5 years of age and decreases to adult values by 15 years.[26]

In a study of six children and adolescents aged 9–16 years, dose- and weight-normalized concentrations of clozapine, another drug that CYP1A2 metabolizes, were similar to those of adults.[27] However, concentrations of the active metabolite norclozapine rose in the pediatric patients. This finding suggested that higher doses were not needed.

Although data are limited, caffeine is a widely used probe for CYP1A2 activity. Therefore, to achieve equivalent target plasma concentrations, we predict that doses (in milligrams/kilogram) for drugs metabolized by CYP1A2 (Table 1) should be reduced by approximately 50% in neonates. Children aged 2–10 years may require doses approximately 50% higher than adults, and adolescents may need doses similar to those prescribed for adults.

CYP2B6

At birth, expression of CYP2B6 is negligible, reaching only 50% of adult values by approximately 1.3 years of age.[22] This isoenzyme metabolizes bupropion, an antidepressant also approved for smoking cessation, to three major metabolites, including hydroxybupropion, an active metabolite. The half-life of bupropion is 66% shorter and its clearance to metabolites is significantly higher in adolescents than in adults.[28,29] Because both the parent drug and its metabolites contribute to the pharmacologic effect, adolescents may not need higher doses. However, due to the shorter half-life, a smaller dosage interval is required. Information regarding the activity of CYP2B6 in neonates, infants, and young children is lacking. Other drugs whose elimination partially depends on CYP2B6 activity are listed in Table 1.

CYP2C9

Activity of CYP2C9 is close to 20% of adult values at birth[30] and reaches 50% by 1 month of age.[31] This activity is genetically determined, with the presence of low-activity alleles varying from 5% among Asians and African-Americans to 40% among Caucasians.

Clearance of warfarin in children younger than 12 years is 44% greater than that observed in older children and adults.[32] Phenytoin is primarily metabolized by CYP2C9 (major pathway) and CYP2C19 (minor pathway).[33] Clearance of phenytoin is approximately twice the adult values in children younger than 6 years and matures by adolescence.[34] Likewise, clearance of celecoxib in children aged 7–16 years is approximately double that reported for adults.[35] Therefore, for children, doses of drugs predominantly metabolized by CYP2C9 (Table 1) may need to be 50–100% higher than those given to adults to achieve equivalent therapeutic concentrations.

CYP2C19

At birth, CYP2C19 activity is approximately 30% of adult activity, which is achieved by 1 year of age.[30] The proton pump inhibitors omeprazole, lansoprazole, and pantoprazole are all primarily metabolized by CYP2C19. Activity of CYP2C19 is genetically determined. The frequency of poor metabolizers varies from 1–2% for Caucasians and African-American to 15–25% for Asians. Clearance of omeprazole and lansoprazole is reduced in neonates; in children older than 1 year, it is similar to clearances found in older children and adults.[36–39] Therefore, weight-corrected doses of drugs predominantly metabolized by CYP2C19 (Table 1) in children older than 1 year are approximately the same as adult doses to achieve equivalent therapeutic concentrations.

CYP2D6

Activity of CYP2D6 is genetically determined. The frequency of poor metabolizers varies from 1–2% in Asians and African-Americans to 6–10% in Caucasians. In the liver, CYP2D6 accounts for only 2% of the CYP content.[40] However, this isoenzyme is responsible for metabolizing more than 40 drugs, including many antidepressants, analgesics, and β-blockers (Table 1).

Activity of CYP2D6 increases rapidly after birth, and, after 2 weeks of age, it does not rise further during the first year of life. Also, by 2 weeks of age, the CYP2D6 phenotype reflects the genotype.[41] The metabolic ratio for dextromethorphan, a marker of CYP2D6 activity, is low in neonates (age < 1 mo) and becomes similar to adult ratios in infants (age 1–12 mo) and children and adolescents aged 3–15 years.[42] Atomoxetine pharmacokinetics are similar to adults in children and adolescents aged 7–14 years.[43] Pharmacokinetics are similar between children and adults for the antidepressants fluoxetine[44] and paroxetine[45] and for the antipsychotic drug risperidone.[46]

Weight-corrected doses of drugs predominantly metabolized by CYP2D6 in neonates must be decreased. However, in infants, children, and adolescents, weight-corrected doses are approximately the same as those given to adults to achieve equivalent therapeutic concentrations.

CYP3A4

The most abundant CYP in the human liver and the intestinal tract is CYP3A4, which accounts for approximately 30% of total hepatic CYP.[40] Its activity increases 3-fold during the first 3 months of life. It has the broadest substrate specificity and is involved in the metabolism of more than 50% of drugs.[47] Activity of CYP3A4 is low at birth. It increases to nearly 20% of adult values at 1 month of age and reaches 72% at 1 year.[48]

Oral clearance of cisapride is decreased in neonates of 28–54 weeks' gestational age.[49] Oral clearance of midazolam is also markedly lower in preterm infants relative to that of younger children,[13] but it is higher in children aged 2–12 years than in adolescents aged 12–16 years.[50] Oral clearance of cyclosporine is approximately 25% higher in children younger than 8 years than those older than 8.[51] Likewise, tacrolimus clearance is elevated 2.7- and 1.9-fold among children aged 1.5–5 and 5–12 years, respectively, compared with clearance in those older than 12 years.[52] Similar age-related increases in the clearance of amlodipine,[53] clonazepam,[54] carbamazepine,[55,56] cyclosporine,[51] lopinavir,[57,58] midazolam[50] and saquinavir[59] have been observed in children.

Weight-corrected doses of drugs predominantly metabolized by CYP3A4 in children must be, on average, 2-fold higher than adult doses to achieve equivalent therapeutic concentrations.

Uridine Diphosphate Glucuronosyltransferases

Activity of UGTs is deficient at birth and reaches adult levels at 2–4 years of age. Unfortunately, little data exist regarding age-related pharmacokinetics of drugs metabolized predominately by means glucuronidation in children. Maturational differences in specific isoenzymes have not yet been determined.

Clearance of zidovudine[60] and lorazepam[61] is decreased in neonates. Oral clearance of ketoprofen (which involves UGT1A1, UGT1A9, UGT2B4, and UGT2B7),[62,63] lorazepam (UGT2B7),[64] zidovudine[65] (UGT2B7), and lamotrigine[66] (UGT1A4) is similar in children and adults. Therefore, weight-corrected doses of drugs predominantly metabolized by glucuronidation must be decreased in neonates. However, to achieve equivalent therapeutic concentrations, doses for children are approximately the same as those adults require.

N-acetyltransferase 2

Activity of NAT2 is genetically determined, with the frequency of slow acetylators varying from 10–20% among Asians to 50–70% among Caucasians. At birth, NAT2 activity is independent of genotype, and the slow-acetylator phenotype predominates. Maturation of the genetically determined, fast-acetylator phenotype in heterozygous and homozygous wild-type individuals develops within the first 4 years of life.[67]

Clearance of isoniazid in children with slowand fast-acetylating phenotypes is similar to that of adults.[68] Procainamide clearance is decreased in neonates;[69] however, weight-adjusted doses in older infants and children are similar to those used in adults.[70] Other drugs metabolized by NAT2 are dapsone, sulfapyridine, and various sulfonamides.

Summary

Metabolism by both CYP and UGTs is low at birth, in the neonatal period, and in infancy. For children, enzymatic activity exceeds adult levels for CY1A2, CYP2C9, and CYP3A4 and diminishes to adult values by puberty. For drugs metabolized by CYP2C19, CYP2D6, UGTs, or NAT2, metabolic activity is similar in children and adults; therefore, children require weightcorrected doses similar to those selected for adults. Information to guide dosing in infants, however, is still unavailable.

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